rivaroxaban for treating pulmonary embolism and preventing
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National Institute for Health and Care Excellence Page 1 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE
Final appraisal determination
Rivaroxaban for treating pulmonary embolism and preventing recurrent venous
thromboembolism
This guidance was developed using the single technology appraisal (STA) process.
1 Guidance
1.1 Rivaroxaban is recommended as an option for treating pulmonary
embolism and preventing recurrent deep vein thrombosis and
pulmonary embolism in adults.
2 The technology
2.1 Rivaroxaban (Xarelto, Bayer) is indicated for the ‘treatment of deep
vein thrombosis and pulmonary embolism, and prevention of
recurrent deep vein thrombosis and pulmonary embolism in adults’.
For the initial treatment of acute pulmonary embolism, the
recommended dosage of rivaroxaban is 15 mg twice daily for the
first 21 days followed by 20 mg once daily for continued treatment
and prevention of recurrent venous thromboembolism.
2.2 Rivaroxaban for the treatment of deep vein thrombosis and
prevention of recurrent deep vein thrombosis and pulmonary
embolism (NICE technology appraisal guidance 261) recommends
National Institute for Health and Care Excellence Page 2 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
rivaroxaban as an option for treating deep vein thrombosis and
preventing recurrent deep vein thrombosis and pulmonary
embolism after a diagnosis of acute deep vein thrombosis in adults.
2.3 The duration of treatment recommended in the summary of product
characteristics depends on bleeding risk and other clinical criteria.
Short-term treatment (3 months) is recommended for people with
transient risk factors such as recent surgery and trauma. Longer
treatment is recommended for people with permanent risk factors,
or idiopathic (unprovoked) deep vein thrombosis or pulmonary
embolism. A reduced dosage of 15 mg twice daily for 21 days
followed by 15 mg once daily should be used in people with
moderate (creatinine clearance 30–49 ml/min) or severe (creatinine
clearance 15–29 ml/min) renal impairment if their risk of bleeding
outweighs the risk for recurrent deep vein thrombosis or pulmonary
embolism.
2.4 The summary of product characteristics lists the following adverse
reactions for rivaroxaban: anaemia, dizziness, headache, fainting,
bleeding events, tachycardia (rapid heartbeat), low blood pressure,
haematoma, stomach pain, dyspepsia (heartburn), nausea,
constipation, diarrhoea, vomiting, pruritus (itching), rash, bruising,
pain in the extremities, fever, and swelling, especially of the ankles
and feet. It also states that people receiving spinal or epidural
anaesthesia may be at increased risk of developing an epidural
haematoma, and that the risk is further increased by the use of
post-operative epidural catheters. For full details of side effects and
contraindications, see the summary of product characteristics.
2.5 Rivaroxaban costs £2.10 per 15-mg or 20-mg tablet (‘British
national formulary’ edition 65). The cost of treatment is estimated to
be £235.86, £427.61 and £811.13 for 3, 6 and 12 months of
National Institute for Health and Care Excellence Page 3 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
treatment respectively. Costs may vary in different settings
because of negotiated procurement discounts.
3 The manufacturer’s submission
The Appraisal Committee (appendix A) considered evidence
submitted by the manufacturer of rivaroxaban and a review of this
submission by the Evidence Review Group (ERG; appendix B).
3.1 The key clinical evidence in the manufacturer’s submission came
from EINSTEIN-PE, an international, event-driven, open-label,
assessor-blind, non-inferiority study. The study included
4832 people in an intention-to-treat population. Treatment duration
was 3, 6 or 12 months and this was determined by a study
investigator before randomisation based on the risk profile of each
person and local preferences. Patients were randomised to either
rivaroxaban 15 mg twice daily for 21 days followed by 20 mg once
daily for the intended treatment duration, or to enoxaparin (a low
molecular weight heparin [LMWH]) 1.0 mg/kg twice daily until
anticoagulation was established plus a vitamin K antagonist (either
warfarin or acenocoumarol), which was dose adjusted to maintain
the international normalised ratio (INR) within a therapeutic range
of 2.0 to 3.0 with a target of 2.5. Enoxaparin was administered for
at least 5 days and was stopped when the INR was more than 2.0
on 2 consecutive measurements at least 24 hours apart. There was
an advised overlap with the vitamin K antagonist of 4 to 5 days.
Patients were assessed during their intended treatment duration,
followed by a 30-day observation period. The manufacturer noted
that there was a difference in the dose of enoxaparin used in the
trial and the dose covered by the European and UK licence (that is,
1.5 mg/kg once daily for at least 5 days and until adequate oral
anticoagulation is established).
National Institute for Health and Care Excellence Page 4 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
3.2 Out of the whole study population, 5.2% were allocated to receive
3 months of treatment, 57.4% to 6 months of treatment and 37.4%
to 12 months of treatment. The median time from onset of
symptoms to randomisation was 4 days. The EINSTEIN-PE study
allowed a limited amount of treatment before randomisation. A
similar proportion of patients in the rivaroxaban arm (92.5%) and
the LMWH/VKA arm (92.1%) received pre-randomisation
anticoagulation (p=0.62, post-hoc binomial test). Among those who
received pre-randomisation anticoagulation, 62.5% of patients
received anticoagulation for 1 day (the maximum duration permitted
was 48 hours).
3.3 In the intention-to-treat population, the mean age was 58 and
approximately 53% of the patients were male. Around 25% of
patients in both treatment arms had a concurrent deep vein
thrombosis. Pulmonary embolism was unprovoked in 65% of
patients receiving rivaroxaban and 64% of patients receiving
LMWH with a vitamin K antagonist (hereafter referred to as
LMWH/VKA). Approximately 5% of people in both treatment arms
had active cancer, and 19% and 20% of people in the rivaroxaban
and LMWH/VKA treatment arms respectively had experienced a
previous venous thromboembolism. EINSTEIN-PE excluded people
with a creatinine clearance of less than 30 ml/min and people for
whom rivaroxaban was not suitable or who had contraindications to
enoxaparin, warfarin or acenocoumarol. A total of 555 (11.5%)
patients discontinued treatment; the number of people who
discontinued was similar in both treatment groups (p=0.07).
3.4 The primary efficacy end point for EINSTEIN-PE was symptomatic
recurrent venous thromboembolism, which was a composite end
point comprising recurrent deep vein thrombosis or pulmonary
embolism. This included both fatal and non-fatal pulmonary
National Institute for Health and Care Excellence Page 5 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
embolism, and unexplained death for which a pulmonary embolism
could not be ruled out. In the intention-to-treat population
(rivaroxaban n=2419; LMWH/VKA n=2413), rivaroxaban met the
pre-specified non-inferiority criterion, which required the upper
bound of the 95% confidence interval of the hazard ratio to be less
than 2. Symptomatic recurrent venous thromboembolism events
occurred in 50 (2.1%) patients in the rivaroxaban arm compared
with 44 (1.8%) patients in the LMWH/VKA arm (hazard ratio [HR]
1.12; 95% confidence interval [CI] 0.75 to 1.68).
3.5 The primary safety outcome for EINSTEIN-PE was clinically
relevant bleeding, that is, major bleeding and clinically relevant
non-major bleeding in the safety population, which consisted of all
patients who had received at least 1 dose of the study drug
(rivaroxaban n=2412; LMWH/VKA n=2405). There was no
difference between rivaroxaban and LMWH/VKA in clinically
relevant bleeding that was experienced by 249 (10.3%) and 274
(11.4%) patients in each treatment arm respectively (HR 0.90,
95% CI 0.76 to 1.07). The proportion of patients who experienced
major bleeding was statistically significantly lower with rivaroxaban
(1.1%) than with LMWH/VKA (2.2%) (HR 0.49, 95% CI 0.31 to
0.79, p=0.003). In the intended treatment period, there were a
similar number of deaths in the rivaroxaban arm (58 deaths) and
the LMWH/VKA arm (50 deaths) (HR 1.13, 95% CI 0.77 to 1.65).
Treatment-emergent adverse events (other than bleeding and
recurrent venous thromboembolism) were similar between the
treatment arms. Approximately 5% of patients in the rivaroxaban
arm and 4% in the LMWH/VKA arm discontinued treatment
because of an adverse event.
3.6 The manufacturer reported a time in therapeutic range for the
comparator LMWH/VKA of 62.7% across all centres. The
National Institute for Health and Care Excellence Page 6 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
manufacturer highlighted that guidelines from the National Patient
Safety Agency and the Scottish Executive Health Department
recommend a time in therapeutic range of at least 60%. It also
noted there was no statistical interaction observed in EINSTEIN-PE
between time in therapeutic range and treatment effect.
3.7 Health-related quality of life was not measured in EINSTEIN-PE.
The manufacturer described 2 measures of treatment satisfaction
that had been measured: the Anti-Clot Treatment Scale (ACTS)
and the Treatment Satisfaction Questionnaire (TSQM). Treatment
satisfaction was not used to derive any of the utility values used in
the economic analysis.
3.8 The manufacturer presented the results for a number of subgroups
considered in EINSTEIN-PE, which included the 3 subgroups
specified in the final scope issued by NICE. These were groups
based on underlying risk of bleeding, provoked compared with
unprovoked venous thromboembolism, and the presence or
absence of cancer. The manufacturer used the intended treatment
duration as a proxy for bleeding risk. The manufacturer tested for a
statistically significant interaction between each subgroup and the
primary efficacy and safety outcomes. The outcomes of the
statistical interaction tests are academic in confidence, so the
results cannot be presented in this document. The manufacturer
also presented graphically the relative efficacy across subgroups,
including the 3 subgroups specified in the final scope issued by
NICE. The manufacturer presented similar results for the major and
clinically relevant non-major bleeding outcome (with the exception
of the idiopathic and non-idiopathic groups). The 95% confidence
intervals surrounding the hazard ratios for all outcomes overlapped
across the subgroups, suggesting a consistency of effect.
National Institute for Health and Care Excellence Page 7 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
3.9 The manufacturer highlighted that in the comparator arm of the
trial, patients with cancer had received LMWH/VKA, whereas
standard care in the UK is LMWH alone. The manufacturer did not
consider it appropriate to conduct a network meta-analysis to
estimate the relative effectiveness of rivaroxaban compared with
LMWH in people with cancer who had experienced a pulmonary
embolism. This was because of the heterogeneity of the studies
assessing long-term treatment of venous thromboembolism in
people with cancer, which the manufacturer had identified and
presented in its submission for NICE technology appraisal
guidance 261.
3.10 The manufacturer constructed a Markov model to evaluate the
consequences of 3-, 6- and 12-month, and lifelong, treatment with
rivaroxaban for preventing recurrent venous thromboembolism in
people who experience an acute pulmonary embolism. The model
used a time horizon of 40 years and a cycle length of 3 months. To
reflect the change in the risk patients experience over time,
different risks were applied in cycle 1 (months 0–3), 2 (months 3–
6), 3 and 4 (months 6–12) and 5 onwards (12 months onwards).
The evaluation was undertaken from an NHS and personal social
services perspective, and costs and utilities were discounted at
3.5% per year after the first year.
3.11 For people initially treated for 3, 6 or 12 months, there were
13 health states including death. The lifelong treatment model
contained an additional state. People entered the model after their
index pulmonary embolism to an on-treatment state in which they
received 3-, 6-, 12-month or lifelong treatment with rivaroxaban or
LMWH/VKA. They then either stayed on treatment; experienced a
recurrent venous thromboembolism (pulmonary embolism or deep
vein thrombosis), experienced an adverse event (clinically relevant
National Institute for Health and Care Excellence Page 8 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
non-major bleed, major intracranial bleed, or major extracranial
bleed), moved to an off-treatment health state, entered a long-term
complication state (for example, chronic thromboembolic
pulmonary hypertension), or died. The additional state in the
lifelong treatment model was for people who had experienced a
deep vein thrombosis in the timeframe of the model and who had
not stopped treatment for other reasons. All patients who
experienced a deep vein thrombosis after their index pulmonary
embolism were at risk of post-thrombotic syndrome. There was not
a separate health state for post-thrombotic syndrome, rather the
consequences of post-thrombotic syndrome were applied as
disutilities and costs to patients in both the on- and off-treatment
post-deep vein thrombosis health states.
3.12 The modelled cohort was adults with an acute pulmonary embolism
who matched the licensed indication, the EINSTEIN-PE trial
population and the stated decision problem. Data from EINSTEIN-
PE were used to inform the clinical effectiveness of treatments and
to derive the transition probabilities used in the model; this was
supplemented with data from the manufacturer's systematic
reviews. All drug acquisition costs and resources associated with
acute treatment hospital stay, monitoring, recurrent
thromboembolic events and adverse events (that is, bleeding
events) were included in the model.
3.13 A validated preference-based measure of quality of life was not
measured in EINSTEIN-PE; the manufacturer derived the utility
values used in the model through systematic review. The
manufacturer assigned a baseline utility value of 0.825 to all
patients with pulmonary embolism entering the model, which was
taken from a survey of the UK general population using a visual
analogue scale rating and adjusted with disutility values for deep
National Institute for Health and Care Excellence Page 9 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
vein thrombosis, pulmonary embolism, extracranial bleed,
intracranial bleed and post-thrombotic syndrome. All people who
had an intracranial bleed moved to a post-intracranial bleed health
state in the next cycle of the model after their bleed. The utility
value assumed for an intracranial bleed was 0.33, which increased
to 0.71 in the post-intracranial bleed state. A disutility due to
warfarin therapy of 0.012 was applied in the LMWH/VKA arm.
3.14 Base-case results were presented for the 3-, 6-, 12-month and
lifelong treatment durations. For the 3-, 6- and 12-month treatment
durations, rivaroxaban dominated LMWH/VKA, that is, rivaroxaban
was less costly and more effective (0.027, 0.013 and 0.019
incremental quality-adjusted life years [QALYs] and a £395.80,
£213.21 and £133.13 reduction in total costs for the 3-, 6- and 12-
month treatment groups respectively). In the lifelong treatment
analysis, rivaroxaban was associated with an incremental cost-
effectiveness ratio (ICER) compared with LMWH/VKA of £13,252
per QALY gained (0.104 incremental QALYs for an extra
£1374.73).
3.15 The manufacturer performed 123 deterministic sensitivity analyses
for each of the 4 durations of treatment. For the 3-, 6- and 12-
month treatments, the net monetary benefit for rivaroxaban
compared with LMWH/VKA was positive for all analyses if the
maximum acceptable ICER was £20,000 per QALY gained. Cost
effectiveness of lifelong treatment with rivaroxaban was most
sensitive to changes in the frequency of INR-monitoring visits,
where the ICER increased from £13,252 per QALY gained to
£27,914 per QALY gained if people have 3, rather than 5, visits in
each quarter after the first. The manufacturer conducted 1 scenario
analysis, in which the time horizon was reduced from 40 to 5 years.
With a 5-year time horizon, rivaroxaban continued to dominate
National Institute for Health and Care Excellence Page 10 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
LMWH/VKA for the 3-, 6- and 12-month treatment durations. For
the lifelong treatment duration, reducing the time horizon to 5 years
decreased the ICER of rivaroxaban compared with LMWH/VKA to
£12,282 per QALY gained. Probabilistic sensitivity analysis
demonstrated that there was a 99.9%, 95.9%, 93.7% and 59.1%
probability that the base-case ICER for the 3-, 6-, and 12-month
and lifelong treatments was lower than £20,000 per QALY gained.
3.16 The ERG considered that overall, the manufacturer's submission
provided an unbiased estimate of the treatment effect of
rivaroxaban. The ERG stated that it was based on a well-conducted
systematic review of clinical effectiveness, which identified
1 relevant randomised controlled trial. It considered the trial to be of
reasonable quality with a low risk of bias.
3.17 The ERG raised concerns that the patient population in the trial
may not be fully representative of the treatment population in the
UK. In particular, it stated that patients with severe renal
impairment (a creatinine clearance of 15–29 ml/min) were excluded
from the trial. The ERG noted that the summary of product
characteristics specifies that rivaroxaban can be used with caution
with dose reductions if needed in this group of patients. The ERG
stated that as these patients are at higher risk of bleeding and were
excluded from the trial, it is possible that the trial may have
underestimated the rate of bleeding that may be seen in clinical
practice with rivaroxaban.
3.18 The ERG noted that the trial only assessed outcomes up to a 12-
month treatment period; therefore, effectiveness and safety of long-
term treatment with rivaroxaban is unknown. The ERG stated that
the manufacturer's Kaplan-Meier plot of cumulative venous
thromboembolism rates suggested a worsening of the relative
National Institute for Health and Care Excellence Page 11 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
hazard of recurrent venous thromboembolism while on rivaroxaban,
compared with LMWH/VKA, towards the end of the 12-month
treatment period. The ERG commented that it is plausible that the
hazard of recurrent venous thromboembolism might worsen further
if treatments are compared in the longer term, particularly if
adherence to rivaroxaban (which does not need the regular
monitoring of vitamin K antagonists) declines. The ERG noted that
the long-term adherence to rivaroxaban may be far lower than the
80% plus observed in most of the patients in EINSTEIN-PE.
3.19 The ERG considered the manufacturer’s subgroup analyses. The
ERG suggested that the outcomes may be worse in the active
cancer group than those seen for other patients because of
increased bleeding risk. The ERG noted that the manufacturer's
presentation of subgroup data suggested consistency across the
subgroups in terms of the relative safety and efficacy. It considered
that because of the small numbers of people in the trial who had
cancer, differences in the incidence of bleeding may not have been
apparent because of the small number of events recorded in each
treatment arm. The ERG also noted the 95% confidence intervals
around the hazard ratio for recurrent venous thromboembolism in
patients with active cancer presented by the manufacturer were
wide, and suggested this indicated that there is uncertainty around
where the true effect lies and that the manufacturer’s analysis of
efficacy in the cancer subgroup should be interpreted with caution.
The ERG had concerns that the manufacturer had used intended
treatment duration as a proxy for both underlying risk of bleeding
and provoked or unprovoked pulmonary embolism. However, it
suggested that there are no robust markers for determining length
of treatment in advance, which suggests that pre-specified
treatment durations may not be a good proxy for other variables.
National Institute for Health and Care Excellence Page 12 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
3.20 The ERG considered the structure adopted for the economic model
to be reasonable, consistent with current clinical understanding of
pulmonary embolism and consistent with the previous economic
evaluations of treatments for venous thromboembolism, such as
the submission for NICE technology appraisal guidance 261. The
ERG also considered that the parameters used in the model were
generally appropriate and that the population used in the model,
drawn from EINSTEIN-PE, is broadly representative of the
pulmonary embolism population in the UK (with the exception that it
did not include people for whom rivaroxaban is contraindicated or
people with severe renal impairment who may still be eligible for
rivaroxaban).
3.21 The ERG noted that all transition probabilities were treatment-
specific in the lifelong model but that there appeared to be an error
in the model, because after 36 months, the probability of recurrent
venous thromboembolism and bleeding events were the same for
rivaroxaban and LMWH/VKA. The ERG stated that the probabilities
of these events after 36 months were not explicitly stated in the
manufacturer's submission. The ERG believed this to be an
unintended error and corrected the model so that the treatment
effect of rivaroxaban after 36 months was applied to the
LMWH/VKA transition probabilities. After this amendment, the
ICER for rivaroxaban compared with LMWH/VKA in the lifelong
treatment analysis was reduced from £13,252 per QALY gained to
£7072 per QALY gained. For all of the subsequent analyses, the
ERG incorporated this correction and referred to this as the
amended base case. The amended probabilistic base-case ICER
for rivaroxaban compared with LMWH/VKA was £7019 per QALY
gained.
National Institute for Health and Care Excellence Page 13 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
3.22 The ERG had concerns about some of the utility values used in the
manufacturer’s model, particularly as some of the sources of utility
values identified and used by the manufacturer were small studies
or did not use the EQ-5D instrument that is the preferred measure
of health related quality of life in adults in NICE’s reference case.
The ERG considered the utility value of 0.33 for an intracranial
bleed, based on a study of 129 people that had used time trade off
rather than the EQ-5D to derive the utility value that the
manufacturer had applied for 3 months in the intracranial bleed
state model, to be low. The ERG identified a prospective,
longitudinal study that suggested a utility value of 0.31 immediately
after an intracranial bleed (stroke), increasing to 0.55 after 1 month
and to 0.61 by 3 months. As the manufacturer had estimated that
rivaroxaban was associated with fewer intracranial bleeds than
LMWH/VKA, the ERG stated that a mid-value of 0.55 for the
intracranial bleed health-state utility value would be a more
conservative assumption. The ERG also questioned the
manufacturer's choice of utility values for post-thrombotic
syndrome. The manufacturer had used a study of 30 healthy
volunteers that had used a standard gamble approach to derive a
utility value of 0.93 for severe post-thrombotic syndrome. However,
the ERG stated that the study of 129 people, which the
manufacturer had used to obtain utility values for some of the
health states in its model including the utility value for an
intracranial bleed, gave a utility value of 0.86 for post-thrombotic
syndrome. The ERG stated that, as people taking rivaroxaban are
more likely to experience post-thrombotic syndrome, the
manufacturer's choice of utility value for post-thrombotic syndrome
was not a conservative assumption.
National Institute for Health and Care Excellence Page 14 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
3.23 The ERG was satisfied that the unit costs used in the economic
model were relevant and had been obtained using suitable
methods. However, it noted that the costs of reversing the effects of
rivaroxaban and warfarin in the case of major bleeding or elective
surgery had not been included and that these may be significant.
The ERG stated that vitamin K, fresh frozen plasma and
prothrombin complex concentrate (PCC) are used to reverse
bleeding events on warfarin but there is no specific antidote for
rivaroxaban. The ERG commented that either activated
recombinant factor VIIa or PCC may be considered to manage
severe and life-threatening bleeding in patients on rivaroxaban. The
ERG's clinical adviser considered that the reversal of bleeding on
warfarin is likely to need less PCC than rivaroxaban, and that
recombinant factor VIIa may be more effective for reversing
rivaroxaban than PCC. The ERG estimated that the cost of treating
a patient weighing 70 kg with recombinant factor VIIa is £19,303.
The ERG also estimated that the cost of treating a bleed while
receiving rivaroxaban with PCC would be £1680, and the maximum
cost for treating a bleed on warfarin with PCC concentrate would be
£1260.
3.24 The ERG conducted the following exploratory analyses:
reduction in assumed frequency of INR-monitoring visits
reduction in mean LMWH treatment length
reduction in the efficacy of rivaroxaban after 12 months in the
lifelong treatment analysis in preventing recurrent venous
thromboembolism
higher hazard of major bleed on rivaroxaban in the lifelong
treatment analysis
higher utility values for the intracranial bleed state
higher mean age of model population
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Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
costs of emergency anticoagulant reversal taken into account in
all cases of major bleeding
a multiple assumption scenario (reduction in assumed frequency
of INR monitoring visits, with a greater proportion of these in
secondary care and a greater proportion of the primary care
monitoring visits led by nurses; reduction in mean LMWH
treatment length; reduction in the efficacy of rivaroxaban after
12 months in the lifelong treatment analysis; higher hazard of
major bleed).
3.25 The ERG noted that the manufacturer had assumed 9 INR-
monitoring visits in the first quarter for people receiving LMWH/VKA
and 5 in each subsequent quarter, and that this was consistent with
what the manufacturer presented for NICE technology appraisal
guidance 261. The ERG highlighted that in NICE technology
appraisal guidance 261, the Committee had concluded that a less
intensive INR-monitoring programme of 6 visits in the first 3 months
followed by 3 visits every quarter thereafter was reasonable and
relevant (when a deep vein thrombosis was the index
thromboembolism). The ERG reduced the frequency of INR-
monitoring visits to 6 visits in the first quarter and 3 in each
subsequent quarter. The ICER for rivaroxaban compared with
LMWH/VKA increased from £7072 in the base case to £17,857 per
QALY gained in the lifelong treatment duration analysis, and went
from dominating LMWH/VKA in the 12-month treatment duration
analysis to having an ICER of £3542 per QALY gained.
Rivaroxaban continued to dominate LMWH/VKA in the 6-month
treatment analysis. The ERG did not present the effect of a
reduced INR-monitoring frequency scenario on the 3-month
treatment analysis. For the lifelong treatment duration analysis, the
ERG assessed a further scenario of 6 visits in the first quarter and
National Institute for Health and Care Excellence Page 16 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
2 in each subsequent quarter. This assumption increased the ICER
for rivaroxaban compared with LMWH/VKA from £7072 to £22,912
per QALY gained.
3.26 Assuming a shorter treatment duration with LMWH from the
manufacturer’s estimate in the base case (derived from the
academic-in-confidence average duration in EINSTEIN-PE) of
either 9, 8 or 6 days was found to have a minimal cost-saving effect
in the 6-month treatment duration analysis. Rivaroxaban continued
to dominate LMWH/VKA regardless of treatment duration with
LMWH. The ERG did not present the effect of assuming the shorter
treatment duration with LMWH on the 3-, 12-month or lifelong
treatment duration analyses.
3.27 As there was uncertainty surrounding the long-term efficacy and
safety of rivaroxaban, the ERG performed scenario analyses that
assessed varying efficacy and safety effects of rivaroxaban. The
hazard ratio for recurrent venous thromboembolism for rivaroxaban
compared with LMWH/VKA was 1.123 for the entirety of the lifelong
treatment base case. The ERG assessed 2 scenarios in which the
hazard ratio was increased to either 1.5 or 2.0 after 12 months (that
is, rivaroxaban was assumed to be increasingly less effective
relative to LMWH/VKA). Assuming a hazard ratio of 1.5 for venous
thromboembolism after 12 months for the population in the lifelong
treatment analysis increased the ICER for rivaroxaban compared
with LMWH/VKA from £7072 to £9043 per QALY gained. When a
hazard ratio of 2.0 was assumed, the ICER for rivaroxaban
compared with LMWH/VKA increased to £14,090 per QALY
gained.
3.28 In the manufacturer’s base-case analyses, the hazard ratio for
major bleed for rivaroxaban compared with LMWH/VKA was 0.493.
National Institute for Health and Care Excellence Page 17 of 45
Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
The ERG assessed 2 scenarios in the lifelong treatment duration
analysis in which the hazard ratio for major bleeds was increased.
In the first scenario, the ERG used a hazard ratio for major bleeds
of 0.65. This was taken from the EINSTEIN-DVT trial (one of the
key trials supporting the clinical effectiveness of rivaroxaban in the
manufacturer’s submission for NICE technology appraisal
guidance 261) that compared rivaroxaban with LMWH/VKA in
preventing recurrent venous thromboembolism in people who had
experienced a deep vein thrombosis. In this scenario, the ICER for
rivaroxaban compared with LMWH/VKA increased from £7072 to
£10,070 per QALY gained for the lifelong treatment duration. In the
second scenario, the ERG used a hazard ratio for major bleeds of
0.79, which was the upper limit of the 95% confidence interval
surrounding the hazard ratio for a major bleed seen in EINSTEIN-
PE. Applying this hazard ratio, the ICER for rivaroxaban compared
with LMWH/VKA increased from £7072 to £14,177 per QALY
gained for the lifelong treatment duration.
3.29 Assuming an increased utility value in the intracranial bleed state
from 0.33 in the base case to 0.55 (see section 3.22) did not
appreciably change the total QALYs and the model outcomes were
hardly altered: rivaroxaban continued to dominate LMWH/VKA for
6- and 12-month treatment durations, and in the lifelong treatment
analysis the ICER increased from £7072 to £7098 per QALY
gained. The ERG did not present the effect of assuming a higher
utility value in the intracranial bleed state on the 3-month treatment
analysis.
3.30 The ERG noted that the base-case analyses used a population with
a mean age of 58 years, which is lower than the mean age of some
other pulmonary embolism and deep vein thrombosis patient
populations described in the literature. However, assuming a higher
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mean age of the model population from 58 years in the base case
to 65 years did not have a large effect on the cost-effectiveness
estimates: rivaroxaban continued to dominate LMWH/VKA for 6-
and 12-month treatment durations, and for a lifelong treatment, the
ICER increased from £7072 to £7911 per QALY gained. The ERG
did not present the effect of assuming a higher mean age of the
model population on the 3-month treatment analysis.
3.31 The ERG assessed 3 scenarios in which the costs of emergency
anticoagulant reversal were taken into account. The first scenario
assumed that all people received PCC in all cases of major
bleeding. This scenario had a modest effect on the base-case
analyses for the 12-month and lifelong treatment durations:
rivaroxaban continued to dominate LMWH/VKA in the 12-month
treatment analysis and the ICER decreased from £7072 to £6868
per QALY gained in the lifelong treatment analysis. The second
scenario assumed that people who had a bleed while taking
LMWH/VKA received PCC, whereas those taking rivaroxaban
received recombinant factor VIIa. This scenario resulted in an ICER
for rivaroxaban compared with LMWH/VKA of £2328 per QALY
gained for the 12-month treatment duration, and increased the
ICER from £7072 to £19,642 per QALY gained for the lifelong
treatment duration. The third scenario assumed the same as the
second scenario in terms of treatments received to reverse major
bleeding but also assumed that the risk of a major bleed with
rivaroxaban was more similar to the risk experienced on
LMWH/VKA (HR 0.65 from EINSTEIN-DVT) and the frequency of
INR monitoring for people receiving LMWH/VKA to be 6 in the first
quarter and 3 in each subsequent quarter. In this scenario, the
ICER increased for the 12-month treatment cohort to £23,364 per
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QALY gained and to £44,046 per QALY gained for lifelong
treatment.
3.32 The ERG’s multiple assumption scenario included a reduction in
the frequency of INR-monitoring visits with a greater proportion
occurring in secondary care (a 50:50 split rather than the
66 primary care to 34 secondary care split as in the manufacturer’s
base case); a greater proportion of primary care monitoring visits
led by nurses (75% rather than 50%); a reduction in LMWH
treatment length; a reduction in rivaroxaban efficacy after
12 months in the lifelong treatment duration analysis; and a raised
hazard of major bleed. After applying these assumptions,
rivaroxaban continued to dominate LMWH/VKA for the 6-month
treatment duration. For the 12-month treatment duration, the ICER
for rivaroxaban compared with LMWH/VKA was £11,590 per QALY
gained, and for the lifelong treatment duration the ICER was
£35,909 per QALY gained. The ERG did not present the effects of
these multiple assumptions on the 3-month treatment analysis.
3.33 Full details of all the evidence are in the manufacturer’s submission
and the ERG report.
4 Consideration of the evidence
4.1 The Appraisal Committee reviewed the data available on the
clinical and cost effectiveness of rivaroxaban, having considered
evidence on the nature of pulmonary embolism and recurrent
thromboembolism and the value placed on the benefits of
rivaroxaban by people with the condition, those who represent
them and clinical specialists. It also took into account the effective
use of NHS resources.
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4.2 The Committee discussed the clinical management of pulmonary
embolism. It noted the statements received from the clinical
specialists, which stated that people with suspected pulmonary
embolism are generally treated with immediate parenteral
anticoagulation, most commonly with a low molecular weight
heparin (LMWH) delivered by subcutaneous injection, and when
the diagnosis has been confirmed, an oral vitamin K antagonist
such as warfarin. The LMWH is continued for at least 5 days or
until the patient's international normalised ratio (INR) has been
within the therapeutic range for at least 24 hours, at which point it is
stopped. The Committee also heard that a minority of people
receive unfractionated heparin or fondaparinux instead of LMWH.
People presenting with pulmonary embolism and haemodynamic
instability may receive thrombolysis (or undergo embolectomy if
thrombolysis is contraindicated) before receiving a vitamin K
antagonist. The Committee discussed the manufacturer’s decision
problem, noting that the manufacturer had excluded fondaparinux
as a comparator even though it was specified in the final scope
issued by NICE. The Committee noted the comments from the
manufacturer and the ERG highlighting that fondaparinux is rarely
used in UK clinical practice. The Committee accepted that
fondaparinux is rarely used and agreed that it was appropriate to
consider only LMWH and a vitamin K antagonist as the comparator
as listed in the manufacturer’s decision problem.
4.3 The Committee considered the treatment duration with
anticoagulation. The Committee was aware that the NICE clinical
guideline 144 on Venous thromboembolic diseases recommends
3 months’ anticoagulation with a vitamin K antagonist for people
with confirmed pulmonary embolism, with treatment continued
beyond 3 months for those with permanent risk factors for venous
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thromboembolism recurrence, taking into account individual risk
factors such as bleeding. However, it noted that approximately 95%
of people in EINSTEIN-PE received anticoagulation for 6 months or
more. The Committee heard from the clinical specialists that
anticoagulation therapy is often started with an expected duration
of therapy, but that clinical evaluation is usually carried out at 3 or
6 months, when a decision is made as to whether or not therapy
should be continued long term. It also heard that pulmonary
embolism is a potentially life-threatening event, and that it would be
unusual for people to be treated for less than 6 months. The clinical
specialists also explained that people who have had a massive
pulmonary embolus, recurrent venous thromboembolism, or are
considered to be at significant risk of recurrence would usually
receive lifelong anticoagulation. The clinical specialists estimated
that overall, as many as 50% of people with pulmonary embolism
would subsequently receive lifelong anticoagulation. The
Committee accepted that although NICE clinical guideline 144
recommends an initial treatment duration of 3 months, the usual
duration of treatment in UK practice was 6 months or more.
4.4 The Committee heard from the patient expert about the perceived
benefits of rivaroxaban for treating pulmonary embolism and
preventing recurrent venous thromboembolic events over the
standard care of LMWH with a vitamin K antagonist (such as
warfarin). The patient expert highlighted the disadvantages of
warfarin, including the need for regular monitoring of INR, and dose
adjustment. Monitoring, which needs regular visits to hospital or GP
appointments, can be costly and inconvenient, and means some
people may have to take time off work. The patient expert said
young people of school or university age may also experience clots
and INR monitoring can lead to disruption of education. The patient
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expert further explained that the burdens of monitoring and dose
adjustments with warfarin may also affect carers of people who
have had a pulmonary embolus and they may have to make
adjustments to their own schedules to enable the person for whom
they are caring to monitor their INR. As warfarin has many drug
interactions, it may be unsuitable for people with comorbidities, and
because of various food interactions, people may need to adjust
and monitor their diet and lifestyle. The patient expert said that
there are some people whose INR is unstable on warfarin or who
are allergic to it, for whom an alternative is needed. The patient
expert highlighted that rivaroxaban can be used at the onset of
pulmonary embolism in primary or secondary care. Rivaroxaban
has the advantage that it avoids injections, regular blood tests and
the diet and lifestyle considerations necessary with the combination
of heparin and warfarin. The patient expert said that patients are
very interested in rivaroxaban and other newer anticoagulants, but
noted that a small proportion of patients are concerned about these
new agents and find regular monitoring of INR reassuring to
confirm that they are adequately anticoagulated. The patient expert
expressed the view that rivaroxaban should be made available as
an additional treatment option. The Committee accepted the
limitations of treatment with LMWH and a vitamin K antagonist and
acknowledged the potential benefits of rivaroxaban.
4.5 The Committee considered the clinical management of bleeding
resulting from treatment with anticoagulants. The clinical specialists
highlighted that there are currently no validated guidelines on how
to treat bleeding experienced while taking the new anticoagulants.
The clinical specialists stated that people who have a bleed while
taking a vitamin K antagonist may receive vitamin K, which takes
8–12 hours to reverse the effect of the vitamin K antagonist. One
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clinical specialist estimated that approximately 0.1% of people
receiving warfarin experience a major bleed and for major bleeds
needing rapid reversal, the most effective treatment is prothrombin
complex concentrate (PCC) that provides correction for 12 hours.
However, PCC would only be considered appropriate for a
proportion of people with a major bleed. The Committee noted that
the Evidence Review Group (ERG) had suggested that
recombinant factor VIIa may be used to reverse a bleed. The
clinical specialists agreed that recombinant factor VIIa may be
used, but as it has a very short duration of action of approximately
2 hours, and is extremely expensive, they considered that PCC
would be used in preference. The Committee further noted that
recombinant factor VIIa is not licensed for the reversal of bleeding
experienced on the new anticoagulants. It heard from the clinical
specialists and the patient expert that there is no established
antidote for rivaroxaban but because of its relatively short half-life,
some bleeds can be managed simply by discontinuing rivaroxaban.
The Committee concluded that there are standard approaches to
stop bleeding experienced while on standard vitamin K antagonists
such as warfarin, but there is uncertainty about the best approach
to reverse bleeding experienced while taking rivaroxaban.
4.6 The Committee considered the generalisability of the EINSTEIN-PE
trial to UK clinical practice. It discussed whether the population in
the trial reflects those seen in UK clinical practice. The Committee
noted that the mean age of the population in the trial was 58 years.
The clinical specialists highlighted that the incidence of deep vein
thrombosis and pulmonary embolism increases with age, but
EINSTEIN-PE included few people over 80 years. The clinical
specialists considered that the proportion of people in the trial with
provoked and unprovoked pulmonary embolism was similar to that
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observed in clinical practice. The Committee noted the ERG’s
concern that EINSTEIN-PE excluded people with severe renal
impairment, even though they may be eligible for treatment with
rivaroxaban with dose adjustment if needed. The clinical specialists
stated that rivaroxaban would probably not be used in routine
clinical practice for people with severe renal impairment. The
Committee heard from the clinical specialists that in their opinion,
the population in EINSTEIN-PE generally reflected the
corresponding UK patient population. The Committee concluded
that the baseline characteristics of the population in EINSTEIN-PE
were generalisable to UK clinical practice.
4.7 The Committee discussed the comparator used in EINSTEIN-PE
and its relevance to UK clinical practice. The clinical specialists
stated the LMWH used in the trial, enoxaparin, has the largest
evidence base of all the LMWHs. The clinical specialists also stated
that there were no known differences in the clinical effectiveness of
the different available LMWHs. The Committee considered whether
the dosage of enoxaparin used in EINSTEIN-PE is applicable to UK
clinical practice. It noted that in EINSTEIN-PE, the US licensed
dose of enoxaparin was used (that is, 1.0 mg/kg twice a day),
whereas the dose used in the UK is 1.5 mg/kg once a day. The
Committee heard from the clinical specialists that the 2 dosages
are similar in terms of efficacy, and although people in EINSTEIN-
PE received a higher overall daily dose of enoxaparin than would
be seen in UK clinical practice, this is not expected to have affected
the generalisability of the trial to the UK. The Committee accepted
that the differences in the dosage did not appear to be clinically
significant and was satisfied that the comparators used in the trial
represented routine and best practice.
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4.8 The Committee considered the time in therapeutic range in the
enoxaparin and vitamin K antagonist arm of the trial. It noted that
the average time in therapeutic range for people receiving
enoxaparin with a vitamin K antagonist was 62.7%. The clinical
specialists stated that time in therapeutic range varies, but a range
of between 60% and 70% would be expected in UK clinical
practice. The Committee therefore concluded that the data from the
enoxaparin with a vitamin K antagonist arm in the trial were
applicable to routine clinical practice.
4.9 The Committee considered the generalisability of the EINSTEIN-PE
trial to the subgroup of patients who have active cancer. The
Committee noted that EINSTEIN-PE included a small proportion of
people with cancer. The clinical specialists stated that people with
cancer who experience venous thromboembolism would currently
receive extended treatment with a LMWH alone, as evidence has
shown that LMWH is more effective than warfarin for this group of
people, and has been shown to reduce mortality. The Committee
noted that the manufacturer had not presented any clinical
evidence for a comparison of LMWH alone with rivaroxaban. The
clinical specialists suggested that, without evidence from a direct
comparison, it was unlikely that clinicians would offer rivaroxaban
as an alternative treatment to LMWH for people with cancer. The
Committee agreed that the comparator treatment in EINSTEIN-PE
that included a vitamin K antagonist did not reflect UK clinical
practice for people with cancer, and there was no evidence for the
relative efficacy of rivaroxaban compared with long-term LMWH,
the standard treatment for these patients. The Committee
concluded that without direct evidence of the relative efficacy of
rivaroxaban compared with LMWH alone, it would be inappropriate
to make a recommendation for this group.
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4.10 The Committee considered the trial design and the clinical-
effectiveness results of the EINSTEIN-PE trial. It noted that the trial
was designed to assess whether rivaroxaban was non-inferior to
LMWH with a vitamin K antagonist for preventing recurrent
thromboembolism after pulmonary embolism and that the
manufacturers had also tested for statistical superiority for the
primary efficacy outcome. The Committee noted that for the whole
trial population, the rates of recurrent venous thromboembolism
were not statistically significantly different in the rivaroxaban and
LMWH with a vitamin K antagonist arms in the trial. The Committee
concluded that rivaroxaban has acceptable clinical effectiveness
compared with low molecular weight heparin and a vitamin K
antagonist.
4.11 The Committee discussed the safety data from EINSTEIN-PE. It
noted that there was no statistically significant difference in the
composite end point of major bleeding and clinically relevant non-
major bleeding between rivaroxaban and LMWH with a vitamin K
antagonist, but that the incidence of major bleeds was statistically
significantly lower with rivaroxaban. The Committee concluded that
rivaroxaban has an acceptable safety profile compared with low
molecular weight heparin and a vitamin K antagonist.
4.12 The Committee considered the results from the treatment duration
subgroups and noted that groups were based on clinical criteria. It
discussed the level of uncertainty around the hazard ratios and
noted that the confidence intervals surrounding the hazard ratio for
recurrent thromboembolism overlapped. It was aware that the
confidence intervals were particularly wide for the 3-month
treatment duration subgroup and noted the analysis was based on
a small number of people recruited to the group (around 5% of the
study population) and on a small number of events in both
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treatment arms. In addition, the Committee heard from the clinical
specialists that they were not aware of any biological reason to
expect a differential effect in the 3-month treatment duration
subgroup. The Committee therefore concluded that evidence of
treatment effect should be based on the whole trial population of
EINSTEIN-PE.
4.13 The Committee considered the issue of long-term or lifelong
treatment with rivaroxaban. It noted that the maximum length of
treatment in EINSTEIN-PE was 12 months, but was mindful that it
had heard from the clinical specialists that some people will need
longer treatment durations in clinical practice (section 4.3). In the
absence of long-term data, the Committee considered the
plausibility of the effects of rivaroxaban being maintained beyond
12 months. The clinical specialists stated that there is no biological
or pharmacological reason why the effects of rivaroxaban should
not be maintained over time but noted that there was uncertainty
about how people would adhere to treatment with rivaroxaban over
the long term. The Committee accepted that there was no
biological or pharmacological reason why the effects of rivaroxaban
would not be maintained over the long term.
4.14 The Committee noted that the manufacturer had presented 4 base-
case scenarios for 3-, 6-, 12-month treatments and a lifelong
treatment analysis. It noted that the economic model used clinical-
effectiveness data from EINSTEIN-PE and utility data derived
through systematic review. The Committee noted that rivaroxaban
dominated treatment with LMWH and a vitamin K antagonist, that
is, was less costly and more effective in the manufacturer’s
deterministic analysis of 3-, 6- and 12-month treatment durations. It
noted that for lifelong treatment, the manufacturer’s base case
incremental cost-effectiveness ratio (ICER) was £13,300 per
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quality-adjusted life year (QALY) gained but after the corrections
made to the model by the ERG, the base case for lifelong treatment
was reduced to £7070 per QALY gained. The Committee noted that
this figure was calculated using the manufacturer’s estimate of INR-
monitoring costs.
4.15 The Committee discussed the estimate of the cost of INR
monitoring. It heard from the clinical specialists that although there
is a trend towards more monitoring being performed in primary
care, some people still receive monitoring in secondary care. The
clinical specialists also stated that there is huge variation in the
frequency of INR monitoring for people receiving a vitamin K
antagonist; some people may need weekly visits, particularly at the
beginning of therapy, and some people may only need INR
monitoring twice a year. The clinical specialists estimated that, as a
guide, on the basis of 1 audit, INR monitoring once every 5–
6 weeks might be a reasonable average estimate. The patient
expert also highlighted that there is interest from patients in self-
monitoring of INR, but there is variation in the availability of INR-
home monitoring machines. The Committee concluded that there is
considerable variability and uncertainty surrounding service
provision and the frequency of INR monitoring that makes
determining an accurate cost of INR monitoring problematic. It
noted that the ERG had assumed fewer INR-monitoring visits than
the manufacturer, which the ERG confirmed resulted in lower first
year monitoring costs of between £304 and £379. The application
of these scenarios to lifelong treatment increased the ICER from
£7070 per QALY gained in the base case to £17,900 and £22,900
per QALY gained respectively. The Committee considered how
INR-monitoring costs had been estimated in previous appraisals. In
Rivaroxaban for the treatment of deep vein thrombosis and
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prevention of recurrent deep vein thrombosis and pulmonary
embolism (NICE technology appraisal guidance 261) the
Committee had considered that after deep venous thrombosis, an
INR-monitoring frequency of 6 visits in the first quarter and 3 in
each subsequent quarter, resulting in first-year costs of £320, to be
reasonable. The Committee took into account the clinical
specialists’ estimates of average INR-monitoring frequency (that is,
every 5–6 weeks) and also the deliberations during technology
appraisal 261 and concluded that the ERG’s scenarios were
reasonable estimations of the impact of INR monitoring on the cost
effectiveness of rivaroxaban, and that the manufacturer’s estimate
of frequency of monitoring visits was too high.
4.16 The Committee discussed the health-related quality of life data
used in the economic model. It noted that health-related quality of
life had not been measured in EINSTEIN-PE and that the
manufacturer had obtained the utility values used in its model
through systematic review. The Committee was aware that the
ERG had considered the utility values used in the economic model
to be generally appropriate; however, the Committee considered
that some of the studies that the manufacturer had used to obtain
the utility values were too small and did not meet the reference
case outlined in NICE’s Guide to the methods of technology
appraisal. The Committee expressed its disappointment that the
manufacturer had not followed the reference case to derive the
utility values. In particular, it noted that only 1 study fully met
NICE’s reference case criteria (that is, the source of data for
measurement of health-related quality of life was reported directly
by patients or carers, the source of preference data for valuation of
changes in health-related quality of life was a representative
sample of the public, and the preferred measure of health-related
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quality of life, the EQ-5D, had been used). The Committee noted
that similar utility values had been used by the manufacturer in its
economic model for NICE technology appraisal guidance 261 and it
also noted that in the scenario analysis carried out by the ERG in
which the utility value for the intracranial bleed state was increased
from 0.33 to 0.55, there was only a minimal effect on the ICER. The
Committee concluded that although the health-related quality of life
studies selected by the manufacturer to obtain utility values for its
economic model did not meet the NICE reference case, the cost-
effectiveness estimates did not appear to be sensitive to the utility
values used.
4.17 The Committee considered the 2 additional scenario analyses
performed by the ERG for lifelong treatment that addressed the
impact of an increase in the risk of a thromboembolic event or a
bleeding event for rivaroxaban after 12 months. The Committee
noted that the worst-case ICER for rivaroxaban compared with
LMWH and a vitamin K antagonist was £14,100 per QALY gained
when the hazard ratio for a recurrent venous thromboembolism
was increased from 1.12 to 2, and £14,200 per QALY gained when
the hazard ratio for a major bleed was increased from 0.49 to 0.79
(the upper limit of the 95% confidence interval for the major bleed
hazard ratio seen in EINSTEIN-PE). The Committee noted that the
ERG had also carried out a multiple assumption scenario that
resulted in an ICER of £35,900. This included the assumption that
both the effectiveness of rivaroxaban in preventing venous
thromboembolic events decreased and the risk of bleeds increased
relative to conventional therapy after 12 months compared with the
base case. The Committee heard from the clinical specialists that if
an anticoagulant was less effective in preventing venous
thromboembolic events, then it would be expected to have a lower
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rate of bleeds. The clinical specialists stated that a scenario in
which both the risk of venous thromboembolism and bleeding
increased was clinically implausible. The Committee concluded that
the ERG’s multiple assumption scenario was not plausible and the
resulting ICER was not appropriate or relevant for this appraisal.
4.18 The Committee considered the 3 scenario analyses undertaken by
the ERG in which the costs of reversing a major bleed had been
incorporated and had been assessed in the 12-month and lifelong
treatment analyses. The Committee noted that in these scenarios,
the ERG had assumed that all people who had a major bleed would
receive either treatment with PCC or recombinant factor VIIa;
however, it was mindful of the testimony from the clinical specialists
that only a proportion of people who had a major bleed would
receive these treatments and PCC would preferentially be used
over recombinant factor VIIa (see section 4.5). The Committee
noted that recombinant factor VIIa is a particularly expensive drug
and that the manufacturer did not consider the costs used by the
ERG for recombinant factor VIIa to be relevant to patients in the
decision problem. The Committee stated that consideration of
bleeding reversal costs was relevant but that the ERG had
presented extreme scenarios because it assumed that all people
who had a major bleed would receive PCC or recombinant factor
VIIa. The Committee agreed that there was too much uncertainty
surrounding the treatment of bleeds experienced while on
anticoagulants to reliably estimate the impact of treatment costs for
reversing bleeding on the cost-effectiveness estimates. The
Committee therefore concluded that the ICERs presented by the
ERG for the 12-month analysis (worst-case scenario £23,400 per
QALY gained) and the lifelong analysis (worst-case scenario
£44,000) were not relevant for this appraisal.
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4.19 The Committee considered that in all scenarios assessed for the 3-,
6- and 12-month treatment durations, rivaroxaban either continued
to dominate, or the ICER compared with LMWH and a vitamin K
antagonist could be considered a cost-effective use of NHS
resources. The Committee concluded that rivaroxaban was cost
effective for treating pulmonary embolism for 3, 6 or 12 months.
4.20 For lifelong treatment, the Committee considered the ERG’s
assumptions about the frequency of INR monitoring to be valid and
concluded that the most plausible ICER for lifelong treatment with
rivaroxaban compared with lifelong treatment with a vitamin K
antagonist after initial treatment with a LMWH was between
£17,900 and £22,900 per QALY gained. The Committee concluded
that rivaroxaban is a cost-effective treatment option for the lifelong
treatment of pulmonary embolism and prevention of recurrent
thromboembolism for people in whom long-term treatment is
indicated.
Summary of Appraisal Committee’s key conclusions
TAXXX Appraisal title: Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Section
Key conclusion
Rivaroxaban is recommended as an option for treating pulmonary embolism and preventing recurrent deep vein thrombosis and pulmonary embolism in adults.
In all scenarios assessed for the 3-, 6- and 12-month treatment durations, rivaroxaban either continued to dominate or the ICER compared with LMWH and a vitamin K antagonist could be considered a cost-effective use of NHS resources. The Committee concluded that rivaroxaban was cost effective for treating pulmonary embolism for 3, 6 or 12 months.
For lifelong treatment, the Committee considered the ERG’s assumptions about the frequency of INR monitoring to be valid and concluded that the most plausible ICER for lifelong treatment was between £17,900 and £22,900 per QALY gained. The Committee concluded that rivaroxaban is a cost-effective treatment option for the lifelong treatment of pulmonary embolism and prevention of recurrent thromboembolism for people in whom
1.1
4.19
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long-term treatment is indicated. 4.20
Current practice
Clinical need of patients, including the
availability of alternative treatments
People with suspected pulmonary embolism are generally treated with immediate parenteral anticoagulation, most commonly with a low molecular weight heparin (LMWH) delivered by subcutaneous injection, and when the diagnosis has been confirmed, an oral vitamin K antagonist such as warfarin. Duration of treatment is based on individual risk of recurrent venous thromboembolism and bleeding. The usual duration of treatment in UK practice is 6 months or more.
4.2, 4.3
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?
Disadvantages of long-term anticoagulation with warfarin include the need for regular monitoring of INR, dose adjustment, multiple food and drug interactions and the impact on people’s lifestyle including cost and inconvenience.
Rivaroxaban avoids injections, regular blood tests and the diet and lifestyle considerations necessary with the combination of heparin and warfarin. It can be used at the onset of pulmonary embolism in primary or secondary care.
4.4
What is the position of the treatment in the pathway of care for the condition?
Rivaroxaban is indicated for the ‘treatment of deep vein thrombosis and pulmonary embolism, and prevention of recurrent deep vein thrombosis and pulmonary embolism in adults’.
2.1
Adverse reactions There was no statistically significant difference in the composite end point of major bleeding and clinically relevant non-major bleeding between rivaroxaban and LMWH with a vitamin K antagonist, but that the incidence of major bleeds was statistically significantly lower with rivaroxaban. The Committee concluded that rivaroxaban has an acceptable safety profile compared with LMWH and a vitamin K antagonist.
4.11
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The EINSTEIN-PE trial was the key trial supporting the clinical effectiveness of rivaroxaban in the manufacturer’s submission.
4.10
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Relevance to general clinical practice in the NHS
The baseline characteristics of the population in EINSTEIN-PE were generalisable to UK clinical practice.
4.6
Uncertainties generated by the evidence
The manufacturer had not presented any clinical evidence for a comparison of rivaroxaban with LMWH alone for people with cancer to reflect UK clinical practice for this group of patients. Therefore, the Committee concluded it would be inappropriate to make a recommendation for this group.
The maximum length of treatment in EINSTEIN-PE was 12 months, but some people will need longer treatment durations in clinical practice. The Committee accepted that there was no biological or pharmacological reason why the effects of rivaroxaban would not be maintained over the long term.
4.9
4.13
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
It was noted that treatment duration was assigned based on clinical criteria. The Committee noted that the confidence intervals surrounding the hazard ratio for recurrent thromboembolism overlapped.
4.12
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The primary efficacy outcome in EINSTEIN-PE was symptomatic recurrent venous thromboembolism. The Committee noted that for the whole trial population, the rates of recurrent venous thromboembolism were not statistically significantly different in the rivaroxaban and LMWH with a vitamin K antagonist arms in the trial. The Committee concluded that rivaroxaban had acceptable clinical effectiveness compared with LMWH and a vitamin K antagonist.
4.10
Evidence for cost effectiveness
Availability and nature of evidence
The manufacturer presented an economic model, which used clinical-effectiveness data from EINSTEIN-PE and utility data derived through systematic review, and presented 4 base-case scenarios for 3-, 6-, 12-month treatments and a lifelong treatment analysis.
4.14
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Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
Uncertainties around and plausibility of assumptions and inputs in the economic model
There is considerable variability and uncertainty surrounding service provision and the frequency of INR monitoring that makes determining an accurate cost of INR monitoring problematic. The Committee took into account the clinical specialists’ estimates, the deliberations during technology appraisal 261 and the ERG’s scenarios and concluded that the manufacturer’s estimate of frequency of monitoring visits was too high and the ERG’s scenarios were reasonable estimates.
The Committee considered that some of the studies that the manufacturer had used to obtain the utility values were too small and did not meet the reference case outlined in NICE’s Guide to the methods of technology appraisal. It concluded that the cost effectiveness of rivaroxaban did not appear to be sensitive to the utility values used.
4.15
4.16
Incorporation of health-related quality-of-life benefits and utility values
Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?
The Committee heard from the patient expert who confirmed regular monitoring of INR, dose adjustment, multiple food and drug interactions with warfarin can impact on people’s lifestyle can be costly and inconvenient. The manufacturer applied a disutility due to warfarin therapy of 0.012 in the LMWH/VKA arm.
4.4, 3.13
Are there specific groups of people for whom the technology is particularly cost effective?
None identified
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Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
What are the key drivers of cost effectiveness?
INR monitoring costs. In the manufacturer’s sensitivity analyses the cost effectiveness of lifelong treatment with rivaroxaban was most sensitive to changes in the frequency of INR-monitoring visits, where the ICER increased from £13,252 per QALY gained to £27,914 per QALY gained if people have 3, rather than 5, visits in each quarter after the first. For lifelong treatment, the Committee considered the ERG’s assumptions about the frequency of INR monitoring to be valid resulting in the ICER for lifelong treatment with rivaroxaban compared with lifelong treatment with a vitamin K antagonist after initial treatment with a LMWH increasing from £7070 in the ERG’s amended base case to between £17,900 and £22,900 per QALY gained.
3.15, 4.15, 4.20
Most likely cost-effectiveness estimate (given as an ICER)
The Committee considered that in all scenarios assessed for the 3-, 6- and 12-month treatment durations, rivaroxaban either continued to dominate or the ICER compared with LMWH and a vitamin K antagonist could be considered a cost-effective use of NHS resources. The most plausible ICER for lifelong treatment with rivaroxaban compared with lifelong treatment with a vitamin K antagonist after initial treatment with a LMWH was between £17,900 and £22,900 per QALY gained.
4.19, 4.20
Additional factors taken into account
Patient access schemes (PPRS)
Not applicable.
End-of-life considerations
Not applicable
Equalities considerations and social value judgements
No equalities issues were raised.
5 Implementation
5.1 Section 7(6) of the National Institute for Health and Care
Excellence (Constitution and Functions) and the Health and Social
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Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
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Care Information Centre (Functions) Regulations 2013 requires
clinical commissioning groups, NHS England and, with respect to
their public health functions, local authorities to comply with the
recommendations in this appraisal within 3 months of its date of
publication.
5.2 When NICE recommends a treatment ‘as an option’, the NHS must
make sure it is available within the period set out in the paragraph
above. This means that, if a patient has pulmonary embolism and
the doctor responsible for their care thinks that rivaroxaban is the
right treatment, it should be available for use, in line with NICE’s
recommendations.
5.3 NICE has developed tools to help organisations put this guidance
into practice (listed below). These are available on our website
(www.nice.org.uk/guidance/TAXXX). [NICE to amend list as
needed at time of publication]
Slides highlighting key messages for local discussion.
Costing template and report to estimate the national and local
savings and costs associated with implementation.
Implementation advice on how to put the guidance into practice
and national initiatives that support this locally.
A costing statement explaining the resource impact of this
guidance.
Audit support for monitoring local practice.
6 Recommendations for further research
6.1 There have been no head-to-head trials of rivaroxaban compared
with a low molecular weight heparin for people who have cancer
and experience an acute pulmonary embolism or deep vein
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Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
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thrombosis. As in NICE technology appraisal guidance 261 it is
recommended that further research should be carried out.
6.2 Research into the long-term treatment effects of rivaroxaban is
needed.
7 Related NICE guidance
Published
Venous thromboembolic diseases: the management of venous
thromboembolic diseases and the role of thrombophilia testing. NICE
clinical guideline 144 (2012).
Rivaroxaban for the treatment of deep vein thrombosis and prevention of
recurrent deep vein thrombosis and pulmonary embolism. NICE technology
appraisal guidance 261 (2012).
Apixaban for the prevention of venous thromboembolism after total hip or
knee replacement in adults. NICE technology appraisal guidance 245
(2012).
Venous thromboembolism: reducing the risk of venous thromboembolism
(deep vein thrombosis and pulmonary embolism) in patients admitted to
hospital. NICE clinical guideline 92 (2010).
Rivaroxaban for the prevention of venous thromboembolism after total hip
or total knee replacement in adults. NICE technology appraisal
guidance 170 (2009).
Dabigatran etexilate for the prevention of venous thromboembolism after
hip or knee replacement surgery in adults. NICE technology appraisal
guidance 157 (2008).
NICE pathways
Venous thromboembolism. NICE pathway (2011).
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Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
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NICE quality standards
Venous thromboembolism prevention. NICE quality standard 3 (2010).
Management of venous thromboembolic diseases. NICE quality
standard 29 (2013).
8 Review of guidance
8.1 The guidance on this technology will be considered for review in
May 2015 alongside the review of NICE technology appraisal
guidance 261. The Guidance Executive will decide whether the
technology should be reviewed based on information gathered by
NICE, and in consultation with consultees and commentators.
Jane Adam
Chair, Appraisal Committee
April 2013
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Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
Appendix A: Appraisal Committee members and NICE
project team
A Appraisal Committee members
The Appraisal Committees are standing advisory committees of NICE.
Members are appointed for a 3-year term. A list of the Committee members
who took part in the discussions for this appraisal appears below. There are
4 Appraisal Committees, each with a chair and vice chair. Each Appraisal
Committee meets once a month, except in December when there are no
meetings. Each Committee considers its own list of technologies, and ongoing
topics are not moved between Committees.
Committee members are asked to declare any interests in the technology to
be appraised. If it is considered there is a conflict of interest, the member is
excluded from participating further in that appraisal.
The minutes of each Appraisal Committee meeting, which include the names
of the members who attended and their declarations of interests, are posted
on the NICE website.
Dr Jane Adam (Chair)
Department of Diagnostic Radiology, St George’s Hospital
Professor Iain Squire (Vice Chair)
Consultant Physician, University Hospitals of Leicester
Professor A E Ades
Professor of Public Health Science, Department of Community Based Medicine, University of Bristol
Professor Thanos Athanasiou
Professor of Cardiovascular Sciences and Cardiac Surgery and Consultant Cardiothoracic Surgeon, Imperial College London and Imperial College Healthcare NHS Trust
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Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
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Dr Gerardine Bryant
General Practitioner, Heartwood Medical Centre, Derbyshire
Dr Fiona Duncan
Clinical Nurse Specialist, Anaesthetic Department, Blackpool Victoria Hospital, Blackpool
Mr Andrew England
Lecturer in Medical Imaging, NIHR Fellow, University of Liverpool
Professor Jonathan Grigg
Professor of Paediatric Respiratory and Environmental Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University London
Dr Brian Hawkins
Chief Pharmacist, Cwm Taf Health Board, South Wales
Dr Peter Heywood
Consultant Neurologist, Frenchay Hospital
Dr Sharon Saint Lamont
Head of Quality and Innovation, North East Strategic Health Authority
Dr Ian Lewin
Consultant Endocrinologist, North Devon District Hospital
Dr Louise Longworth
Reader in Health Economics, HERG, Brunel University
Dr Anne McCune
Consultant Hepatologist, University Hospitals Bristol NHS Foundation Trust
Professor John McMurray
Professor of Medical Cardiology, University of Glasgow
Dr Mohit Misra
General Practitioner, Queen Elizabeth Hospital, London
Ms Sarah Parry
CNS Paediatric Pain Management, Bristol Royal Hospital for Children
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Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
Dr Ann Richardson
Lay Member
Dr Paul Robinson
Medical Director, Merck Sharp & Dohme
Ms Ellen Rule
Programme Director, NHS Bristol
Mr Stephen Sharp
Senior Statistician, MRC Epidemiology Unit
Dr Peter Sims
General Practitioner, Devon
Mr David Thomson
Lay Member
Dr John Watkins
Clinical Senior Lecturer / Consultant in Public Health Medicine, Cardiff University and National Public Health Service Wales
Dr Olivia Wu
Reader in Health Economics, University of Glasgow
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Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
Issue date: April 2013
B NICE project team
Each technology appraisal is assigned to a team consisting of 1 or more
health technology analysts (who act as technical leads for the appraisal), a
technical adviser and a project manager.
Mary Hughes
Technical Lead
Nicola Hay
Technical Adviser
Bijal Joshi
Project Manager
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Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
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Appendix B: Sources of evidence considered by the
Committee
A The Evidence Review Group (ERG) report for this appraisal was
prepared by Southampton Health Technology Assessments Centre
(SHTAC):
Copley V, Pickett K, Cooper K et al. Rivaroxaban for the treatment of pulmonary embolism and the prevention of recurrent venous thromboembolism. A single technology appraisal. February 2013
B The following organisations accepted the invitation to participate in this
appraisal as consultees and commentators. They were invited to
comment on the draft scope. Organisations listed in I were also invited to
make written submissions. Organisations listed in II gave their expert
views on rivaroxaban by providing a written statement to the Committee.
Organisations listed in I, II and III have the opportunity to appeal against
the final appraisal determination.
I Manufacturer/sponsor
Bayer (rivaroxaban)
II Professional/specialist and patient/carer groups:
AntiCoagulation Europe (ACE) British Society for Haematology British Society for Haemostasis and Thrombosis Clinical Leaders of Thrombosis (CLOT) Lifeblood: The Thrombosis Charity Royal College of Nursing Royal College of Pathologists Royal College of Physicians United Kingdom Clinical Pharmacy Association Vascular Society
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Final appraisal determination – Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism
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III Other consultees:
Department of Health Welsh Government
IV Commentator organisations (did not provide written evidence and
without the right of appeal):
Commissioning Support Appraisals Service Department of Health, Social Services and Public Safety for
Northern Ireland Healthcare Improvement Scotland National Clinical Guidelines Centre National Institute for Health Research Health Technology
Assessment Programme Southampton Health Technology Assessment Centre,
University of Southampton
C The following individuals were selected from clinical specialist and
patient expert nominations from the consultees and commentators. They
gave their expert personal view on rivaroxaban by providing oral
evidence to the Committee.
Dr David Bevan, Consultant Haematologist and Clinical Lead in Haemostasis, nominated by organisation representing Royal College of Pathologists and British Society for Haematology – clinical specialist
Dr Mark Crowther, Consultant Haematologist, nominated by organisation representing British Society of Haemostasis and Thrombosis – clinical specialist
Mrs Annya Stephens-Boal, Executive Officer of Lifeblood: The Thrombosis Charity, nominated by organisation representing Lifeblood: The Thrombosis Charity – patient expert
D Representatives from the following manufacturer/sponsor attended
Committee meetings. They contributed only when asked by the
Committee chair to clarify specific issues and comment on factual
accuracy.
Bayer
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